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3 Library of Congress Cataloging-in-Publication Data Coffee, tea, chocolate, and the brain / edited by Astrid Nehlig. p. ; cm. (Nutrition, brain, and behavior ; v. 2) Includes bibliographical references and index. ISBN (hardback : alk. paper) 1. Caffeine Physiological effect. 2. Coffee Physiological effect. 3. Tea Physiological effect. 4. Chocolate Physiological effect. 5. Neurochemistry. 6. Brain Effect of drugs on. [DNLM: 1. Brain drug effects. 2. Coffee Physiology. 3. Cacao physiology. 4. Caffeine pharmacology. 5. Cognition drug effects. 6. Tea physiology. WB 438 C ] I. Nehlig, Astrid. II. Series. QP801.C24 C dc This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage or retrieval system, without prior permission in writing from the publisher. All rights reserved. Authorization to photocopy items for internal or personal use, or the personal or internal use of specific clients, may be granted by CRC Press LLC, provided that $1.50 per page photocopied is paid directly to Copyright clearance Center, 222 Rosewood Drive, Danvers, MA USA. The fee code for users of the Transactional Reporting Service is ISBN /04/$0.00+$1.50. The fee is subject to change without notice. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. The consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for resale. Specific permission must be obtained in writing from CRC Press LLC for such copying. Direct all inquiries to CRC Press LLC, 2000 N.W. Corporate Blvd., Boca Raton, Florida Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation, without intent to infringe. Visit the CRC Press Web site at No claim to original U.S. Government works International Standard Book Number Library of Congress Card Number Printed in the United States of America Printed on acid-free paper

4 Preface This book is the second in the series Nutrition, Brain and Behavior. The purpose of this series is to provide a forum whereby basic and clinical scientists can share their knowledge and perspectives regarding the role of nutrition in brain function and behavior. The breadth and diversity of the topics covered in this book make it of great interest to specialists working on coffee/caffeine/tea/chocolate research, to nutritionists and physicians, and to anyone interested in obtaining objective information on the consequences of the consumption of coffee, tea, and chocolate on the brain. Coffee is a very popular beverage, the second most frequently consumed after water. Likewise, tea is a fundamental part of the diet of Asian countries and the U.K. and is becoming progressively more popular in Western countries. Chocolate is also widely consumed all over the world. The pleasure derived from the consumption of coffee, tea, and chocolate is accompanied by a whole range of effects on the brain, which may explain their attractiveness and side effects. Coffee, tea, and chocolate all contain methylxanthines, mainly caffeine, and a large part of their effects on the brain are the result of the presence of these substances. As part of this series on nutrition, the brain, and behavior, the present book brings new information to the long-debated issue of the beneficial and possible negative effects on the brain from the consumption of coffee, tea, or chocolate. Most of the book is devoted to the effects of coffee or caffeine, which constitute the majority of the literature and research on these topics. Much less is known about the other constituents in roasted coffee or about the effects of tea or chocolate on the brain. In this book, we have selected world specialists to update our knowledge on the effects of these three methylxanthine-containing substances. Together with a collection of the data on the effects of coffee and caffeine on sleep, cognition, memory and performance, and mood, this book contains specific information on new avenues of research, such as the effect of caffeine on Parkinson s disease, ischemia, and seizures, and on the mostly unknown effects of the chlorogenic acids found in coffee. The effects of caffeine on the stress axis and development of the brain are also updated. Finally, the potential for addiction to coffee, caffeine, and chocolate is debated, as well as both the possible headache-inducing effect of chocolate consumption and the alleviating effect of caffeine on various types of headaches. Altogether, these updates and new findings are reassuring and rather positive, showing again that moderate coffee, tea, or chocolate consumption has mostly beneficial effects and can contribute to a balanced and healthy diet. We would like to take this opportunity to thank all the authors for their excellent contributions and cooperation in the preparation of this book. Astrid Nehlig, Ph.D. Strasbourg, France Editor Chandan Prasad, Ph.D. New Orleans, Louisiana, USA Series Editor

5 Editor Astrid Nehlig, Ph.D., earned a master s degree in physiology and two Ph.D. degrees in physiology and functional neurochemistry from the scientific University of Nancy, France. She is a research director at the French Medical Research Institute, INSERM, in Strasbourg. Her main research interests are brain metabolism, brain development, the effects of coffee and caffeine on the brain, and temporal lobe epilepsy. She has authored or co-authored approximately 200 articles, books, and book chapters and has been invited to deliver more than 50 lectures at international meetings and research centers. She has received several grants for her work, mainly from the Medical Research Foundation, NATO, and private companies, and a 2002 award from the American Epilepsy Society. Dr. Nehlig has spent two years in the United States working in a highly recognized neuroimaging laboratory at the National Institute for Mental Health in Bethesda, Maryland. She has led an INSERM research team of 10 to 15 persons for 20 years, resulting in the education of more than 15 Ph.D. students and several postdoctoral fellows. She is on the editorial board of the international journal Epilepsia and is a member of the commission of neurobiology of the International League Against Epilepsy and of the French Society of Cerebral Blood Flow and Metabolism. She is also the scientific advisor of PEC (Physiological Effects of Coffee), the European Scientific Association of the Coffee Industry. She acts as an expert for numerous scientific journals and international societies, such as NATO, the British Wellcome Trust, and the Australian Medical Research Institute.

10 1 Mechanisms of Action of Caffeine on the Nervous System John W. Daly and Bertil B. Fredholm CONTENTS Introduction Potential Sites of Action Adenosine Receptors: Blockade by Caffeine Inhibition of Phosphodiesterases by Caffeine Ion Channels: I. Effects of Caffeine on Calcium Ion Channels: II. Effects of Caffeine on GABA A and Glycine Receptors Other Effects of Caffeine Conclusions References INTRODUCTION Because of its presence in popular drinks, caffeine is doubtlessly the most widely consumed of all behaviorally active drugs (Serafin, 1996; Fredholm et al., 1999). Although caffeine is the major pharmacologically active methylxanthine in coffee and tea, cocoa and chocolate contain severalfold higher levels of theobromine than caffeine, along with trace amounts of theophylline. Paraxanthine is a major metabolite of caffeine in humans, while theophylline is a minor metabolite. Thus, not only caffeine, but also the other natural methylxanthines are relevant to effects in humans. In animal models, caffeine, theophylline, and paraxanthine are all behavioral stimulants, whereas the effects of theobromine are weak (Daly et al., 1981). Caffeine, theophylline, and theobromine have been or are used as adjuncts or agents in medicinal formulations. Methylxanthines have been used to treat bronchial asthma (Serafin, 1996), apnea of infants (Bairam et al., 1987; Serafin 1996), as cardiac stimulants (Ahmad and Watson, 1990), as diuretics (Eddy and Downes, 1928), as adjuncts with analgesics (Sawynok and Yaksh, 1993; Zhang, 2001), in electroconvulsive therapy (Coffey et al., 1990), and in combination with ergotamine for treatment of migraine (Diener et al., 2002). An herbal dietary supplement containing ephedrine and caffeine is used as an anorectic (Haller et al., 2002). Other potential therapeutic targets for caffeine include diabetes (Islam et al., 1998; Islam, 2002), Parkinsonism (Schwarzschild et al., 2002), and even cancer (Lu et al., 2002). Caffeine has been used as a diagnostic tool for malignant hyperthermia (Larach, 1989). Clinical uses of caffeine have been reviewed (Sawynok, 1995). In the following chapter, we will focus on the actions of caffeine on the nervous system.

11 POTENTIAL SITES OF ACTION Three major mechanisms must be considered with respect to the actions of caffeine on the peripheral and central nervous system: (1) blockade of adenosine receptors, in particular A 1 - and A 2A -adenosine receptors; (2) blockade of phosphodiesterases, regulating levels of cyclic nucleotides; and (3) action on ion channels, in particular those regulating intracellular levels of calcium and those regulated by the inhibitory neurotransmitters g-aminobutyric acid (GABA) and glycine (Fredholm, 1980; Daly, 1993; Nehlig and Debry, 1994; Fredholm et al., 1997, 1999; Daly and Fredholm, 1998). Caffeine s effects are biphasic. The stimulatory behavioral effects in humans (and rodents) become manifest with plasma levels of 5 to 20 mm, whereas higher doses are depressant. The only sites of action where caffeine would be expected to have a major pharmacological effect at levels of 5 to 20 mm are the A 1 - and the A 2A -adenosine receptors, where caffeine is a competitive antagonist (Daly and Fredholm, 1998). Major effects at other sites of action, such as phosphodiesterases (inhibition), GABA and glycine receptors (blockade), and intracellular calcium-release channels (sensitization to activation by calcium) would be expected to require at least tenfold higher in vivo levels of caffeine. At such levels, toxic effects of caffeine, often referred to at nonlethal levels as caffeinism in humans, become manifest. Convulsions and death can occur at levels above 300 mm. However, it cannot be excluded that subtle effects of 5 to 20 mm caffeine at sites of action other than adenosine receptors might have some relevance to both acute and chronic effects of caffeine. Extensive in vitro studies of the actions of caffeine at such sites are usually performed at concentrations of caffeine of 1 mm or more, clearly levels that in vivo are lethal. ADENOSINE RECEPTORS: BLOCKADE BY CAFFEINE Four adenosine receptors have been cloned and pharmacologically characterized: A 1 -, A 2A -, A 2B -, and A 3 -adenosine receptors (Fredholm et al., 2000, 2001a). Of these the A 3 -adenosine receptor in rodent species has very low sensitivity to blockade by theophylline, with K i values of 100 mm or more (Ji et al., 1994). Human A 3 -adenosine receptors are somewhat more sensitive to xanthines, but at in vivo levels of 5 to 20 mm caffeine will have virtually no effect even on the human A 3 receptors. By contrast, results from rodents and humans show that caffeine binds to A 1, A 2A, or A 2B receptors with K d values in the range of 2 to 20 mm (see Fredholm et al., 1999, 2001b). Thus, caffeine at the levels reached during normal human consumption could exert its actions at A 1, A 2A, or A 2B receptors, but not by blocking A 3 receptors. If caffeine is to exert its actions by blocking adenosine receptors, a prerequisite is that there be a significant ongoing (tonic) activation of A 1, A 2A, or A 2B receptors. All the evidence suggests that at these receptors, adenosine is the important endogenous agonist (Fredholm et al., 1999, 2000, 2001b). Only at A 3 receptors does inosine seem to be a potential agonist candidate (Jin et al., 1997; Fredholm et al., 2001b). In his original proposal of P1 (adenosine) and P2 (ATP) receptors, Burnstock (1978) included the provision that the adenosine receptors would be blocked by theophylline, while the ATP receptors would be insensitive to theophylline. However, there have also been reports of ATP responses that are inhibited by theophylline (Silinksy and Ginsberg, 1983; Shinozuka et al., 1988; Ikeuchi et al., 1996; Mendoza-Fernandez et al., 2000). Such effects have been suggested to indicate novel receptors or to be caused by heteromeric association of A 1 - adenosine and P2Y receptors (Yoshioka et al., 2001). However, the most parsimonious explanation is that the effects are due to rapid breakdown of ATP to adenosine and actions on classical adenosine receptors (Masino et al., 2002). Therefore, caffeine (as well as theophylline and paraxanthine) should act by antagonizing the actions of endogenous adenosine at A 1, A 2A, or A 2B receptors. This requires that the endogenous levels be sufficiently high to ensure an ongoing tonic activation. In the case of A 1 and A 2A receptors, this requirement is fulfilled, at least at those locations where the receptors are abundantly expressed (Fredholm et al., 1999, 2001a,b). By contrast, A 2B receptors may not be expressed at sufficiently high abundance to ensure tonic activation by endogenous adenosine during physiological conditions. It must, however, be remembered that the potency of

12 an agonist is not a fixed value but depends on factors such as receptor number and also the effect studied (Kenakin, 1995). It is therefore interesting to note that when activation of mitogen-activated protein kinases is studied, adenosine is as potent on A 2B as on A 1 and A 2A receptors (Schulte and Fredholm, 2000). Hence, the idea that A 2B receptors are low-affinity receptors activated only at supraphysiological levels of adenosine may not be absolutely true. Nevertheless, the available evidence suggests that most of the effects of caffeine are best explained by blockade of tonic adenosine activation of A 1 and A 2A receptors. In chapters to follow, the relative roles of the different adenosine receptor subtypes in mediating in vivo effects of caffeine will be discussed. Here it will suffice to point out that blockade of A 1 receptors by caffeine could remove either a G i input to adenylyl cyclase or tonic effects mediated through G b,g on calcium release, potassium channels, and voltage-sensitive calcium channels. Conversely, blockade of A 2A -adenosine receptors could remove stimulatory input to adenylyl cyclase. In the complex neuronal circuitry of the central nervous system, the ultimate effects will depend on the site and nature of physiological input by endogenous adenosine. Hints about the biological roles of adenosine are also provided by the distribution of the receptors. Adenosine A 1 receptors are found all over the brain and spinal cord (Fastbom et al., 1986; Jarvis et al., 1987; Weaver, 1996; Svenningsson et al., 1997a; Dunwiddie and Masino, 2001). In the adult rodent and human brain, levels are particularly high in the hippocampus, cortex, and cerebellum. By contrast, A 2A receptors have a much more restricted distribution, being present in high amounts only in the dopamine-rich regions of the brain, including the nucleus caudatus, putamen, nucleus accumbens, and tuberculum olfactorium (Jarvis et al., 1989; Parkinson and Fredholm, 1990; Svenningsson et al., 1997b, 1998, 1999a; Rosin et al., 1998). They are virtually restricted to the GABAergic output neurons that compose the so-called indirect pathway and that also are characterized by expressing enkephalin and dopamine D 2 receptors. There is, indeed, very strong evidence for a close functional relationship between A 2A and D 2 receptors (Svenningsson et al., 1999a). The adenosine A 1 receptors appear to play two major roles: (1) activation of potassium channels leading to hyperpolarization and to decreased rates of neuronal firing and (2) inhibition of calcium channels leading to decreased neurotransmitter release. This will lead to inhibition of excitatory neurotransmission, and there is good evidence for interactions between A 1 and NMDA receptors (Harvey and Lacey, 1997; de Mendonça and Ribeiro, 1993). Adenosine A 2A receptors regulate the function of GABAergic neurons of the basal ganglia. The effects are opposite those of dopamine acting at D 2 receptors. It is now clear that these receptors are predominantly involved in the stimulant effects of caffeine (Svenningsson et al., 1995; El Yacoubi et al., 2000). The two caffeine metabolites, theophylline and paraxanthine, are even more potent inhibitors of adenosine receptors than the parent compound (Svenningsson et al., 1999a; Fredholm et al., 2001b). Therefore, the weighted sum of all of them must be considered when evaluating the effective concentration of antagonist at the adenosine receptors. Investigation of roles of adenosine receptors has been greatly facilitated by the development of a wide variety of potent and/or selective antagonists. Some are xanthines, deriving from caffeine and theophylline as lead compounds, while others are based on other compounds containing instead of a purine other heterocyclic ring systems (Hess, 2001). In addition, the development of receptor knock-out mice has been instrumental in our current understanding. Thus, experiments using A 2A knock-out mice have conclusively shown that blockade of striatal A 2A receptors is the reason why caffeine can induce its behaviorally stimulant effects (Ledent et al., 1997; El Yacoubi et al., 2000) and the mechanisms involved have been clarified in considerable molecular detail (Svenningsson et al., 1999b; Lindskog et al., 2002). In addition, A 2A knock-out mice showed increased aggressiveness and anxiety (Ledent et al., 1997), a characteristic shared by A 1 knock-out mice (Johansson et al., 2001). The fact that elimination of either receptor leads to anxiety could provide the basis for the well-known fact that anxiety is produced by high doses of caffeine in humans (Fredholm et al., 1999); whereas A 2A knock-out mice showed hypoalgesia, A 1 knock-out mice showed

13 hyperalgesia. Finally, using A 1 and A 2A knock-out mice it was shown that at least part of the behaviorally depressant effect of higher doses of caffeine depends on a mechanism other than adenosine receptor blockade (Halldner-Henriksson et al., 2002). INHIBITION OF PHOSPHODIESTERASES BY CAFFEINE The potentiation of a hormonal response by caffeine or theophylline (Butcher and Sutherland, 1962) was considered for years as a criterion for involvement of cyclic AMP in the response, and such xanthines became the prototypic phosphodiesterase inhibitors. Both caffeine and theophylline now are considered rather weak and nonselective phosphodiesterase inhibitors, requiring concentrations far above 5 to 20 mm for significant inhibition of such enzymes (Choi et al., 1988). In 1970, it was demonstrated that caffeine/theophylline blocked adenosine-mediated cyclic AMP formation (Sattin and Rall, 1970), and attention shifted to the importance of adenosine receptor blockade in the effects of alkylxanthines. Agents have been sought that would be selective either towards phosphodiesterases or towards adenosine receptors (Daly, 2000). It has been proposed that the behavioral depressant effects of xanthines are due to inhibition of phosphodiesterases, while the behavioral stimulation by caffeine and other xanthines is due to blockade of adenosine receptors (Choi et al., 1988; Daly, 1993). Indeed, many nonxanthine phosphodiesterase inhibitors are behavioral depressants (Beer et al., 1972). The depressant effects of high concentrations of caffeine will depend, as with any centrally active agent, on the specific neuronal pathways that are affected. The central pathways where there might be a further elevation of cyclic AMP, due to inhibition of phosphodiesterase by caffeine, have not been defined. A limited number of xanthines and other agents that are selective towards different subtypes of phosphodiesterases are available (Daly, 2000). Unfortunately, many have other activities, such as blockade of adenosine receptors, that decrease their utility as research tools. ION CHANNELS: I. EFFECTS OF CAFFEINE ON CALCIUM Caffeine at high concentrations has been reported to have a multitude of effects on calcium channels, transporters, and modulatory sites (Daly, 2000). Caffeine has been known for more than four decades to cause muscle contracture due to release of intracellular calcium. It is now known that caffeine enhances the calcium-sensitivity of a cyclic ADP-ribose-sensitive calcium release channel, the socalled ryanodine-sensitive channel, thereby causing release of intracellular calcium from storage sites in the sarcoplasmic reticulum of muscle and the endoplasmic reticulum of muscle and other cells, including neuronal cells (McPherson et al., 1991; Galione, 1994). Caffeine has been extensively used as a research tool to investigate in vitro the role of release of calcium stores through what is now called the ryanodine-sensitive receptor. In pancreatic b-cells, caffeine-induced calcium release appears to depend on elevated camp (Islam et al., 1998). In most cases, significant release of calcium from storage sites in cells or in isolated sarcoplasmic reticulum has required concentrations of caffeine of 1 mm or higher. However, it is uncertain whether slight acute or chronic effects of low concentrations of caffeine on intracellular calcium might have a significant functional impact on the central nervous system. Caffeine targets not only the ryanodine-sensitive calciumrelease channel, but has also been reported to have effects on several other entities that are involved in calcium homeostasis (Daly, 2000). These include inhibition of IP 3 -induced release of calcium from intracellular storage sites (Parker and Ivorra, 1991; Brown et al., 1992; Missiaen et al., 1992, 1994; Bezprozvanny et al., 1994; Ehrlich et al., 1994; Hague et al., 2000; Sei et al., 2001; however, see Teraoka et al., 1997) and/or inhibition of receptor-mediated IP 3 formation (Toescu et al., 1992; Seo et al., 1999). Both require millimolar concentrations of caffeine. Caffeine at high millimolar concentrations appears to elicit influx of calcium in several cell types (Avidor et al., 1994; Guerrero et al., 1994; Ufret-Vincenty et al., 1995; Sei et al., 2001; Cordero and Romero, 2002); the nature of the channels is unknown. A functional coupling of the caffeine-sensitive calcium-release channels

14 and the voltage-sensitive L-type calcium channels has been reported in neurons (Chavis et al., 1996). Caffeine at millimolar concentrations has been reported to inhibit L-type calcium channels (Kramer et al., 1994; Yoshino et al., 1996). Evidence suggesting both activation and inhibition of L-type calcium channels by caffeine has been reported for pancreatic b-cells, and the former was attributed to inhibition of K ATP channels (Islam et al., 1995). Caffeine at high concentrations reduces uptake of calcium into cardiac mitochondria (Sardão et al., 2002). As yet, no xanthines have been developed with high potency/selectivity for the ryanodinesensitive calcium release channels for use as tools to probe possible significance of the inhibition of this channel by caffeine (see Daly, 2000; Shi et al., 2003 and references therein). Ryanodine, 4-chloro-m-cresol, and eudistomins represent other compounds that activate ryanodine receptors, but ryanodine and the cresol are too toxic for in vivo studies, while eudistomins have poor solubility and hence availability for in vivo studies. ION CHANNELS: II. EFFECTS OF CAFFEINE ON GABA A AND GLYCINE RECEPTORS Caffeine has been known for two decades to interact with GABA A receptors, based primarily on the inhibition by caffeine and theophylline of binding of benzodiazepine agonists to that receptor in brain membranes (Marangos et al., 1979). The binding of a benzodiazepine antagonist, RO , also is inhibited (Davies et al., 1984). However, the IC 50 values for caffeine were about 350 mm at such benzodiazepine sites. A variety of evidence suggests that blockade of GABA A receptors is responsible for the convulsant activity of high doses of caffeine (Amabeoku, 1999; also see Daly, 1993) but is not involved in behavioral stimulation observed at low dosages of caffeine. There are other reported effects of caffeine and/or theophylline on binding of ligands to the GABA A receptor, including reversal of the inhibitory effect of GABA on binding of a convulsant, (+/ )-t-butylcyclophosphothionate (TBPS) (Squires and Saederup, 1987), a slight stimulatory effect on binding of TBPS (Shi et al., 2003), and an inhibition of binding of GABA (Ticku and Birch, 1980) or of the GABA antagonist SR (Shi et al., 2003) to the GABA site. It appears likely that caffeine at high concentrations affects GABA A receptors in a complex, allosteric manner. Functionally, caffeine at 50 mm was reported to inhibit the chloride flux elicited in synaptoneurosomes by a GABA agonist, muscimol (Lopez et al., 1989). At a higher 100 mm concentration, caffeine had no effect, suggestive of a bell-shaped dose-response curve. In the same study with mice, relatively low doses of caffeine (20 mg/kg) appeared to reduce GABA A receptor-mediated responses, measured ex vivo with muscimol in synaptoneurosomes. Functional inhibition of GABA A receptors, in such studies, might involve inhibition of the GABA receptor by elevated calcium, resulting from caffeine-induced release from intracellular calcium stores (Desaulles et al., 1991; Kardos and Blandl, 1994). In hippocampal neurons inhibition of GABA receptor-elicited chloride currents by millimolar concentrations of caffeine did not appear to involve elevation of calcium (Uneyama et al., 1993). Caffeine was almost tenfold more potent in inhibiting glycine-elicited chloride currents with an IC 50 of 500 mm. Further studies on inhibition of glycine responses do not seem to have been forthcoming. In toto, the low potency of caffeine at GABA A receptors makes it unlikely that such effects contribute to the behavioral stimulant effects of caffeine. However, it is possible that subtle blocking effects at GABA receptors could contribute to both acute and chronic effects by affecting the role of inhibitory GABA- and glycine-neuronal pathways. Apparent alterations in GABAergic activities have been reported after chronic caffeine intake in rodents (Mukhopadhyay and Poddar, 1998, 2000). Chronic caffeine intake does result in changes in receptors for several neurotransmitters, including GABA A receptors (Shi et al., 1993), but whether such alterations are the result of direct effects or are downstream of effects at adenosine receptors is unknown. No xanthines selective for GABA A receptors have been forthcoming, and other agents that interact with the GABA A receptor channel complex do not appear suitable as research tools to investigate the unique functional significance of complex interactions of caffeine with GABA receptors.

15 OTHER EFFECTS OF CAFFEINE There are a wide range of other effects of caffeine on ion channels (Reisser et al., 1996; Schroder et al., 2000; Teramoto et al., 2000; Kotsias and Venosa, 2001), enzymes (see Daly, 1993), including lipid and protein kinases (Foukas et al., 2002) and cell cycles (Jiang et al., 2000; Qi et al., 2002), but virtually all require high concentrations of caffeine (see Daly, 1993, 2000 and references therein). Such effects are probably not relevant to the behavioral stimulant properties of caffeine that occur at plasma levels of 5 to 20 mm. There are peripheral effects of caffeine, some perhaps mediated through adenosine receptors and others through inhibition of phosphodiesterase, that could indirectly affect the function of the central nervous system. Conversely, certain peripheral effects of caffeine may be centrally mediated. The elevation of plasma levels of epinephrine by moderate doses of caffeine in humans was noted as early as the 1960s (see Robertson et al., 1978). The released epinephrine appears likely to be responsible for the caffeine-elicited reduction in insulin sensitivity in humans (Keijzers et al., 2002; Thong and Graham, 2002). The mechanism by which caffeine elicits release of epinephrine from adrenal gland appears likely to be due to increases in sympathetic input, since direct effects of caffeine on release of catecholamines from adrenal chromaffin cells requires millimolar concentrations (Ohta et al., 2002). Thus, direct effects on release of epinephrine from the adrenal gland seem unlikely in human studies. Caffeine also increases free fatty acids (Kogure et al., 2002; Thong and Graham, 2002), presumably in part through blockade of A 1 -adenosine receptors on adipocytes. Theophylline has been proposed to induce histone deacetylase activity, thereby reducing gene transcription and, for instance, cytokine-mediated inflammatory responses, apparently by mechanisms not involving adenosine receptors or inhibition of phosphodiesterases (Ito et al., 2002). In vivo effects of caffeine on expression of nitric oxide synthetase and Na + /K + ATPase in rat kidney have been reported (Lee et al., 2002). Whether there are similar effects in the central nervous system is unknown. Caffeine, in addition to increasing plasma epinephrine, increases corticosterone and renin (Robertson et al., 1978; Uhde et al., 1984), an effect often associated with stress (see Henry and Stephens, 1980). CONCLUSIONS Caffeine and other methylxanthines are potentially able to affect a large number of molecular targets. Nevertheless, the current best evidence indicates that the only effect in the central nervous system that is relevant at lower doses of caffeine is blockade of A 1 and A 2A receptors. Higher doses that are related to toxicity and depressant effects appear to exert their effects, at least in part, by mechanisms other than adenosine receptor blockade. REFERENCES Ahmad, R.A. and Watson, R.D. (1990) Treatment of postural hypotension. A review. Drugs, 39, Amabeoku, G.J. (1999) Gamma-aminobutyric acid and glutamic acid receptors may mediate theophyllineinduced seizures in mice. General Pharmacology, 32, Avidor, T., Clementi, E., Schwartz, L. and Atlas, D. (1994) Caffeine-induced transmitter release is mediated via ryanodine-sensitive channel. Neuroscience Letters, 165, Bairam, A., Boutroy, M.J., Badonnel, Y. and Vert, P. (1987) Theophylline versus caffeine: comparative effects in treatment of idiopathic apnea in the preterm infant. Journal of Pediatrics, 110, Beer, B., Chasin, M., Clody, D.E., Vogel, J.R. and Horovitz, Z.P. (1972) Cyclic adenosine monophosphate phosphodiesterase in brain: effect on anxiety. Science, 176, Bezprozvanny, I., Bezprozvannaya, S. and Ehrlich B.E. (1994) Caffeine-induced inhibition of inositol (1,4,5)- trisphosphate-gated calcium channels from cerebellum. Molecular Biology of the Cell, 5,

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